Crohn's disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear
acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand
DNA (dsDNA) shed from sites of intestinal
inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine
colitis and CD patients. The level of exosomal dsDNA, including
mtDNA and nDNA, significantly increased in murine
colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the
STING pathway was verified in CD. EVs from the plasma of active human CD triggered
STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise
inflammation in macrophages via activating the
STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in
STING-deficient mice and macrophages.
STING deficiency significantly ameliorated
colitis. Besides, potential
therapeutic effects of
GW4869, an inhibitor of EVs release were assessed. The application of
GW4869 successfully ameliorated murine
colitis by inhibiting
STING activation. In conclusion, exosomal dsDNA was found to promote intestinal
inflammation via activating the
STING pathway in macrophages and act as a potential mechanistic
biomarker and therapeutic target of CD.